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Hippocampal Proteomic Analysis Reveals Distinct Pathway Deregulation Profiles at Early and Late Stages in a Rat Model of Alzheimer’s-Like Amyloid Pathology

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Abstract

The cerebral accumulation and cytotoxicity of amyloid beta (Aβ) is central to Alzheimer’s pathogenesis. However, little is known about how the amyloid pathology affects the global expression of brain proteins at different disease stages. In order to identify genotype and time-dependent significant changes in protein expression, we employed quantitative proteomics analysis of hippocampal tissue from the McGill-R-Thy1-APP rat model of Alzheimer-like amyloid pathology. McGill transgenic rats were compared to wild-type rats at early and late pathology stages, i.e., when intraneuronal Aβ amyloid burden is conspicuous and when extracellular amyloid plaques are abundant with more pronounced cognitive deficits. After correction for multiple testing, the expression levels of 64 proteins were found to be considerably different in transgenic versus wild-type rats at the pre-plaque stage (3 months), and 86 proteins in the post-plaque group (12 months), with only 9 differentially regulated proteins common to the 2 time-points. This minimal overlap supports the hypothesis that different molecular pathways are affected in the hippocampus at early and late stages of the amyloid pathology throughout its continuum. At early stages, disturbances in pathways related to cellular responses to stress, protein homeostasis, and neuronal structure are predominant, while disturbances in metabolic energy generation dominate at later stages. These results shed new light on the molecular pathways affected by the early accumulation of Aβ and how the evolving amyloid pathology impacts other complex metabolic pathways.

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References

  1. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G et al (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127

    Article  PubMed  Google Scholar 

  2. Sperling R, Johnson K (2013) Biomarkers of Alzheimer disease: current and future applications to diagnostic criteria. Continuum (Minneap Minn) 19:325–338

    Google Scholar 

  3. Wong CW, Quaranta V, Glenner GG (1985) Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related. Proc Natl Acad Sci U S A 82:8729–8732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM (1986) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261:6084–6089

    CAS  PubMed  Google Scholar 

  5. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A 85:4051–4055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Terry RD (2006) Alzheimer’s disease and the aging brain. J Geriatr Psychiatry Neurol 19:125–128

    Article  PubMed  Google Scholar 

  7. McGeer EG, McGeer PL (2010) Neuroinflammation in Alzheimer’s disease and mild cognitive impairment: a field in its infancy. J Alzheimers Dis 19:355–361

    Article  PubMed  CAS  Google Scholar 

  8. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344

    Article  CAS  PubMed  Google Scholar 

  9. Reiman EM, Quiroz YT, Fleisher AS, Chen K, Velez-Pardo C, Jimenez-Del-Rio M, Fagan AM, Shah AR et al (2012) Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol 11:1048–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S et al (2014) Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 13:614–629

    Article  PubMed  Google Scholar 

  11. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292

    Article  PubMed  PubMed Central  Google Scholar 

  12. Klyubin I, Cullen WK, Hu N-W, Rowan MJ (2012) Alzheimer’s disease Aβ assemblies mediating rapid disruption of synaptic plasticity and memory. Molecular Brain 5:25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I et al (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95:6448–6453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539

    Article  CAS  PubMed  Google Scholar 

  15. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH (2005) Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 8:79–84

    Article  CAS  PubMed  Google Scholar 

  16. Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357

    Article  PubMed  CAS  Google Scholar 

  17. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ (2011) Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A 108:5819–5824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang J, Dickson DW, Trojanowski JQ, Lee VM (1999) The levels of soluble versus insoluble brain Abeta distinguish Alzheimer’s disease from normal and pathologic aging. Exp Neurol 158:328–337

    Article  CAS  PubMed  Google Scholar 

  20. Näslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571–1577

    Article  PubMed  Google Scholar 

  21. Aggarwal K, Choe LH, Lee KH (2006) Shotgun proteomics using the iTRAQ isobaric tags. Brief Funct Genomic Proteomic 5:112–120

    Article  CAS  PubMed  Google Scholar 

  22. Zieske LR (2006) A perspective on the use of iTRAQ reagent technology for protein complex and profiling studies. J Exp Bot 57:1501–1508

    Article  CAS  PubMed  Google Scholar 

  23. Fu Y, Zhao D, Pan B, Wang J, Cui Y, Shi F, Wang C, Yin X et al (2015) Proteomic analysis of protein expression throughout disease progression in a mouse model of Alzheimer’s disease. J Alzheimers Dis 47:915–926

    Article  CAS  PubMed  Google Scholar 

  24. Sun Y, Rong X, Lu W, Peng Y, Li J, Xu S, Wang L, Wang X (2015) Translational study of Alzheimer’s disease (AD) biomarkers from brain tissues in AβPP/PS1 mice and serum of AD patients. J Alzheimers Dis 45:269–282

    CAS  PubMed  Google Scholar 

  25. Lv J, Ma S, Zhang X, Zheng L, Ma Y, Zhao X, Lai W, Shen H et al (2014) Quantitative proteomics reveals that PEA15 regulates astroglial Aβ phagocytosis in an Alzheimer’s disease mouse model. J Proteome 110:45–58

    Article  CAS  Google Scholar 

  26. Ciavardelli D, Silvestri E, Del Viscovo A, Bomba M, De Gregorio D, Moreno M, Di Ilio C, Goglia F et al (2010) Alterations of brain and cerebellar proteomes linked to Aβ and tau pathology in a female triple-transgenic murine model of Alzheimer’s disease. Cell Death Dis 1:e90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Martin B, Brenneman R, Becker KG, Gucek M, Cole RN, Maudsley S (2008) iTRAQ analysis of complex proteome alterations in 3xTgAD Alzheimer’s mice: understanding the interface between physiology and disease. PLoS One 3:e2750

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Sizova D, Charbaut E, Delalande F, Poirier F, High AA, Parker F, Van Dorsselaer A, Duchesne M et al (2007) Proteomic analysis of brain tissue from an Alzheimer’s disease mouse model by two-dimensional difference gel electrophoresis. Neurobiol Aging 28:357–370

    Article  CAS  PubMed  Google Scholar 

  29. Takano M, Yamashita T, Nagano K, Otani M, Maekura K, Kamada H, Tsunoda S, Tsutsumi Y et al (2013) Proteomic analysis of the hippocampus in Alzheimer’s disease model mice by using two-dimensional fluorescence difference in gel electrophoresis. Neurosci Lett 534:85–89

    Article  CAS  PubMed  Google Scholar 

  30. Musunuri S, Wetterhall M, Ingelsson M, Lannfelt L, Artemenko K, Bergquist J, Kultima K, Shevchenko G (2014) Quantification of the brain proteome in Alzheimer’s disease using multiplexed mass spectrometry. J Proteome Res 13:2056–2068

    Article  CAS  PubMed  Google Scholar 

  31. Zahid S, Oellerich M, Asif AR, Ahmed N (2014) Differential expression of proteins in brain regions of Alzheimer’s disease patients. Neurochem Res 39:208–215

    Article  CAS  PubMed  Google Scholar 

  32. Chen S, Lu FF, Seeman P, Liu F (2012) Quantitative proteomic analysis of human substantia nigra in Alzheimer’s disease, Huntington’s disease and multiple sclerosis. Neurochem Res 37:2805–2813

    Article  CAS  PubMed  Google Scholar 

  33. Donovan LE, Higginbotham L, Dammer EB, Gearing M, Rees HD, Xia Q, Duong DM, Seyfried NT et al (2012) Analysis of a membrane-enriched proteome from postmortem human brain tissue in Alzheimer’s disease. Proteomics Clin Appl 6:201–211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Aluise CD, Robinson RA, Beckett TL, Murphy MP, Cai J, Pierce WM, Markesbery WR, Butterfield DA (2010) Preclinical Alzheimer disease: brain oxidative stress, Abeta peptide and proteomics. Neurobiol Dis 39:221–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vercauteren FG, Clerens S, Roy L, Hamel N, Arckens L, Vandesande F, Alhonen L, Janne J et al (2004) Early dysregulation of hippocampal proteins in transgenic rats with Alzheimer’s disease-linked mutations in amyloid precursor protein and presenilin 1. Brain Res Mol Brain Res 132:241–259

    Article  CAS  PubMed  Google Scholar 

  36. Yang H, Wittnam JL, Zubarev RA, Bayer TA (2013) Shotgun brain proteomics reveals early molecular signature in presymptomatic mouse model of Alzheimer’s disease. J Alzheimers Dis 37:297–308

    CAS  PubMed  Google Scholar 

  37. Hong I, Kang T, Yoo Y, Park R, Lee J, Lee S, Kim J, Song B et al (2013) Quantitative proteomic analysis of the hippocampus in the 5XFAD mouse model at early stages of Alzheimer’s disease pathology. J Alzheimers Dis 36:321–334

    CAS  PubMed  Google Scholar 

  38. Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, Vercauteren F, Atifeh R et al (2010) A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis 20:113–126

    Article  CAS  PubMed  Google Scholar 

  39. Iulita MF, Allard S, Richter L, Munter LM, Ducatenzeiler A, Weise C, Do Carmo S, Klein WL et al (2014) Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study. Acta Neuropathol Commun 2:61

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wilson EN, Abela AR, Do Carmo S, Allard S, Marks AR, Welikovitch LA, Ducatenzeiler A, Chudasama Y et al (2017) Intraneuronal amyloid beta accumulation disrupts hippocampal CRTC1-dependent gene expression and cognitive function in a rat model of Alzheimer disease. Cereb Cortex 27:1501–1511

  41. Whishaw IQ, Metz GA, Kolb B, Pellis SM (2001) Accelerated nervous system development contributes to behavioral efficiency in the laboratory mouse: a behavioral review and theoretical proposal. Dev Psychobiol 39:151–170

    Article  CAS  PubMed  Google Scholar 

  42. Do Carmo S, Cuello AC (2013) Modeling Alzheimer’s disease in transgenic rats. Mol Neurodegener 8:37

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Masuda T, Tomita M, Ishihama Y (2008) Phase transfer surfactant-aided trypsin digestion for membrane proteome analysis. J Proteome Res 7:731–740

    Article  CAS  PubMed  Google Scholar 

  44. Gilar M, Olivova P, Daly AE, Gebler JC (2005) Two-dimensional separation of peptides using RP-RP-HPLC system with different pH in first and second separation dimensions. J Sep Sci 28:1694–1703

    Article  CAS  PubMed  Google Scholar 

  45. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol 57:289–300

    Google Scholar 

  46. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A et al (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43(Database issue):D447–D452

    Article  CAS  PubMed  Google Scholar 

  47. Forman HJ, Zhang H, Rinna A (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Asp Med 30:1–12

    Article  CAS  Google Scholar 

  48. Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P et al (2013) Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12:207–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ et al, Dominantly Inherited Alzheimer Network (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367:795–804

  50. Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT et al (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66:75–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yamamoto M, Kensler TW (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 278:8135–8145

    Article  CAS  PubMed  Google Scholar 

  52. Sharma R, Yang Y, Sharma A, Awasthi S, Awasthi YC (2004) Antioxidant role of glutathione S-transferases: protection against oxidant toxicity and regulation of stress-mediated apoptosis. Antioxid Redox Signal 6:289–300

    Article  CAS  PubMed  Google Scholar 

  53. Resende R, Moreira PI, Proença T, Deshpande A, Busciglio J, Pereira C, Oliveira CR (2008) Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic Biol Med 44:2051–2057

    Article  CAS  PubMed  Google Scholar 

  54. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H et al (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767

    Article  CAS  PubMed  Google Scholar 

  55. Nunomura A, Perry G, Pappolla MA, Friedland RP, Hirai K, Chiba S, Smith MA (2000) Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J Neuropathol Exp Neurol 59:1011–1017

    Article  CAS  PubMed  Google Scholar 

  56. Behl C, Davis JB, Lesley R, Schubert D (1994) Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77:817–827

    Article  CAS  PubMed  Google Scholar 

  57. Matsuoka Y, Picciano M, La Francois J, Duff K (2001) Fibrillar beta-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer’s disease. Neuroscience 104:609–613

    Article  CAS  PubMed  Google Scholar 

  58. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, Tabaton M, Perry G (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70:2212–2215

    Article  CAS  PubMed  Google Scholar 

  59. Mohmmad Abdul H, Sultana R, Keller JN, St Clair DK, Markesbery WR, Butterfield DA (2006) Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer’s disease. J Neurochem 96:1322–1335

    Article  PubMed  CAS  Google Scholar 

  60. Butterfield DA, Swomley AM, Sultana R (2013) Amyloid β-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid Redox Signal 19:823–835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O et al (2002) Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 10:279–288

    Article  CAS  PubMed  Google Scholar 

  62. Frederikse PH, Garland D, Zigler JS Jr, Piatigorsky J (1996) Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta has toxic effects on lens epithelial cells. J Biol Chem 271:10169–10174

    Article  CAS  PubMed  Google Scholar 

  63. Tan JL, Li QX, Ciccotosto GD, Crouch PJ, Culvenor JG, White AR, Evin G (2013) Mild oxidative stress induces redistribution of BACE1 in non-apoptotic conditions and promotes the amyloidogenic processing of Alzheimer’s disease amyloid precursor protein. PLoS One 8:e61246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S et al (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A 98:5856–5861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rikans LE, Hornbrook KR (1997) Lipid peroxidation, antioxidant protection and aging. Biochim Biophys Acta 1362:116–127

    Article  CAS  PubMed  Google Scholar 

  66. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G et al (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416:507–511

    Article  CAS  PubMed  Google Scholar 

  67. Young JC, Barral JM, Ulrich Hartl F (2003) More than folding: localized functions of cytosolic chaperones. Trends Biochem Sci 28:541–547

    Article  CAS  PubMed  Google Scholar 

  68. Song Y, Masison DC (2005) Independent regulation of Hsp70 and Hsp90 chaperones by Hsp70/Hsp90-organizing protein Sti1 (Hop1). J Biol Chem 280:34178–34185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gezen-Ak D, Dursun E, Hanağası H, Bilgiç B, Lohman E, Araz ÖS, Atasoy IL, Alaylıoğlu M et al (2013) BDNF, TNFα, HSP90, CFH, and IL-10 serum levels in patients with early or late onset Alzheimer’s disease or mild cognitive impairment. J Alzheimers Dis 37:185–195

    CAS  PubMed  Google Scholar 

  70. Owen JB, Di Domenico F, Sultana R, Perluigi M, Cini C, Pierce WM, Butterfield DA (2009) Proteomics-determined differences in the concanavalin-A-fractionated proteome of hippocampus and inferior parietal lobule in subjects with Alzheimer’s disease and mild cognitive impairment: implications for progression of AD. J Proteome Res 8:471–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Di Domenico F, Sultana R, Tiu GF, Scheff NN, Perluigi M, Cini C, Butterfield DA (2010) Protein levels of heat shock proteins 27, 32, 60, 70, 90 and thioredoxin-1 in amnestic mild cognitive impairment: an investigation on the role of cellular stress response in the progression of Alzheimer disease. Brain Res 1333:72–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Luo W, Sun W, Taldone T, Rodina A, Chiosis G (2010) Heat shock protein 90 in neurodegenerative diseases. Mol Neurodegener 5:24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Gao Y, Thomas JO, Chow RL, Lee GH, Cowan NJ (1992) A cytoplasmic chaperonin that catalyzes beta-actin folding. Cell 69:1043–1050

    Article  CAS  PubMed  Google Scholar 

  74. Yaffe MB, Farr GW, Miklos D, Horwich AL, Sternlicht ML, Sternlicht H (1992) TCP1 complex is a molecular chaperone in tubulin biogenesis. Nature 358:245–248

    Article  CAS  PubMed  Google Scholar 

  75. Khabirova E, Moloney A, Marciniak SJ, Williams J, Lomas DA, Oliver SG, Favrin G, Sattelle DB et al (2014) The TRiC/CCT chaperone is implicated in Alzheimer’s disease based on patient GWAS and an RNAi screen in Aβ-expressing Caenorhabditis elegans. PLoS One 9:e102985

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Johnson RJ, Xiao G, Shanmugaratnam J, Fine RE (2001) Calreticulin functions as a molecular chaperone for the beta-amyloid precursor protein. Neurobiol Aging 22:387–395

    Article  CAS  PubMed  Google Scholar 

  77. Williams DB (2006) Beyond lectins: the calnexin/calreticulin chaperone system of the endoplasmic reticulum. J Cell Sci 119:615–623

    Article  CAS  PubMed  Google Scholar 

  78. Lin Q, Cao Y, Gao J (2014) Serum calreticulin is a negative biomarker in patients with Alzheimer’s disease. Int J Mol Sci 15:21740–21753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ahn SG, Thiele DJ (2003) Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev 17:516–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Adachi M, Liu Y, Fujii K, Calderwood SK, Nakai A, Imai K, Shinomura Y (2009) Oxidative stress impairs the heat stress response and delays unfolded protein recovery. PLoS One 4:e7719

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Manalo DJ, Lin Z, Liu AY (2002) Redox-dependent regulation of the conformation and function of human heat shock factor 1. Biochemistry 41:2580–2588

    Article  CAS  PubMed  Google Scholar 

  82. Butterfield DA, Poon HF, St Clair D, Keller JN, Pierce WM, Klein JB, Markesbery WR (2006) Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer’s disease. Neurobiol Dis 22:223–232

    Article  CAS  PubMed  Google Scholar 

  83. Shen L, Chen C, Yang A, Chen Y, Liu Q, Ni J (2015) Redox proteomics identification of specifically carbonylated proteins in the hippocampi of triple transgenic Alzheimer’s disease mice at its earliest pathological stage. J Proteome 123:101–113

    Article  CAS  Google Scholar 

  84. Qi Y, Klyubin I, Harney SC, Hu N, Cullen WK, Grant MK, Steffen J, Wilson EN et al (2014) Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents. Acta Neuropathol Commun 2:175

    Article  PubMed  PubMed Central  Google Scholar 

  85. Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC et al (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci U S A 96:3228–3233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421

    Article  CAS  PubMed  Google Scholar 

  87. Hardy J (2009) The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J Neurochem 110:1129–1134

    Article  CAS  PubMed  Google Scholar 

  88. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    Article  CAS  PubMed  Google Scholar 

  89. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27:2866–2875

    Article  CAS  PubMed  Google Scholar 

  90. Shankar GM, Walsh DM (2009) Alzheimer’s disease: synaptic dysfunction and Abeta. Mol Neurodegener 4:48

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464

    Article  CAS  PubMed  Google Scholar 

  92. Scheff SW, DeKosky ST, Price DA (1990) Quantitative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiol Aging 11:29–37

    Article  CAS  PubMed  Google Scholar 

  93. Knafo S, Alonso-Nanclares L, Gonzalez-Soriano J, Merino-Serrais P, Fernaud-Espinosa I, Ferrer I, DeFelipe J (2009) Widespread changes in dendritic spines in a model of Alzheimer’s disease. Cereb Cortex 19:586–592

    Article  CAS  PubMed  Google Scholar 

  94. Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT (2005) Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 25:7278–7287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Tsai J, Grutzendler J, Duff K, Gan WB (2004) Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 7:1181–1183

    Article  CAS  PubMed  Google Scholar 

  96. Grutzendler J, Helmin K, Tsai J, Gan WB (2007) Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease. Ann N Y Acad Sci 1097:30–39

    Article  PubMed  Google Scholar 

  97. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27:796–807

    Article  CAS  PubMed  Google Scholar 

  98. Arendt T (2001) Alzheimer’s disease as a disorder of mechanisms underlying structural brain self-organization. Neuroscience 102:723–765

    Article  CAS  PubMed  Google Scholar 

  99. Geddes JW, Monaghan DT, Cotman CW, Lott IT, Kim RC, Chui HC (1985) Plasticity of hippocampal circuitry in Alzheimer’s disease. Science 230:1179–1181

    Article  CAS  PubMed  Google Scholar 

  100. Masliah E, Mallory M, Hansen L, Alford M, Albright T, DeTeresa R, Terry R, Baudier J et al (1991) Patterns of aberrant sprouting in Alzheimer’s disease. Neuron 6:729–739

    Article  CAS  PubMed  Google Scholar 

  101. Rekart JL, Quinn B, Mesulam MM, Routtenberg A (2004) Subfield-specific increase in brain growth protein in postmortem hippocampus of Alzheimer’s patients. Neuroscience 126:579–584

    Article  CAS  PubMed  Google Scholar 

  102. Zhang XM, Cai Y, Xiong K, Cai H, Luo XG, Feng JC, Clough RW, Struble RG et al (2009) Beta-secretase-1 elevation in transgenic mouse models of Alzheimer’s disease is associated with synaptic/axonal pathology and amyloidogenesis: implications for neuritic plaque development. Eur J Neurosci 30:2271–2283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Heggland I, Storkaas IS, Soligard HT, Kobro-Flatmoen A, Witter MP (2015) Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer’s disease. Eur J Neurosci 41:1245–1262

    Article  PubMed  Google Scholar 

  104. Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250:279–282

    Article  CAS  PubMed  Google Scholar 

  105. Mucke L, Masliah E, Johnson WB, Ruppe MD, Alford M, Rockenstein EM, Forss-Petter S, Pietropaolo M et al (1994) Synaptotrophic effects of human amyloid beta protein precursors in the cortex of transgenic mice. Brain Res 666:151–167

    Article  CAS  PubMed  Google Scholar 

  106. Bell KF, Zheng L, Fahrenholz F, Cuello AC (2008) ADAM-10 over-expression increases cortical synaptogenesis. Neurobiol Aging 29:554–565

    Article  CAS  PubMed  Google Scholar 

  107. Norris CM, Scheff SW (2009) Recovery of afferent function and synaptic strength in hippocampal CA1 following traumatic brain injury. J Neurotrauma 26:2269–2278

    Article  PubMed  PubMed Central  Google Scholar 

  108. Mosconi L, Andrews RD, Matthews DC (2013) Comparing brain amyloid deposition, glucose metabolism, and atrophy in mild cognitive impairment with and without a family history of dementia. J Alzheimers Dis 35:509–524

    CAS  PubMed  Google Scholar 

  109. Dubois A, Herard AS, Delatour B, Hantraye P, Bonvento G, Dhenain M, Delzescaux T (2010) Detection by voxel-wise statistical analysis of significant changes in regional cerebral glucose uptake in an APP/PS1 transgenic mouse model of Alzheimer’s disease. NeuroImage 51:586–598

    Article  PubMed  Google Scholar 

  110. Nicholson RM, Kusne Y, Nowak LA, LaFerla FM, Reiman EM, Valla J (2010) Regional cerebral glucose uptake in the 3xTG model of Alzheimer’s disease highlights common regional vulnerability across AD mouse models. Brain Res 1347:179–185

    Article  CAS  PubMed  Google Scholar 

  111. Sorbi S, Bird ED, Blass JP (1983) Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol 13:72–78

    Article  CAS  PubMed  Google Scholar 

  112. Butterfield DA, Reed T, Newman SF, Sultana R (2007) Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment. Free Radic Biol Med 43:658–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Butterfield DA, Sultana R (2007) Redox proteomics identification of oxidatively modified brain proteins in Alzheimer’s disease and mild cognitive impairment: insights into the progression of this dementing disorder. J Alzheimers Dis 12:61–72

    Article  CAS  PubMed  Google Scholar 

  114. Ashraf A, Fan Z, Brooks DJ, Edison P (2015) Cortical hypermetabolism in MCI subjects: a compensatory mechanism? Eur J Nucl Med Mol Imaging 42:447–458

    Article  CAS  PubMed  Google Scholar 

  115. Cohen AD, Price JC, Weissfeld LA, James J, Rosario BL, Bi W, Nebes RD, Saxton JA et al (2009) Basal cerebral metabolism may modulate the cognitive effects of Abeta in mild cognitive impairment: an example of brain reserve. J Neurosci 29:14770–14778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Morbelli S, Perneczky R, Drzezga A, Frisoni GB, Caroli A, van Berckel BN, Ossenkoppele R, Guedj E et al (2013) Metabolic networks underlying cognitive reserve in prodromal Alzheimer disease: a European Alzheimer disease consortium project. J Nucl Med 54:894–902

    Article  CAS  PubMed  Google Scholar 

  117. Haier RJ, Alkire MT, White NS, Uncapher MR, Head E, Lott IT, Cotman CW (2003) Temporal cortex hypermetabolism in Down syndrome prior to the onset of dementia. Neurology 61:1673–1679

    Article  CAS  PubMed  Google Scholar 

  118. Chou JL, Shenoy DV, Thomas N, Choudhary PK, Laferla FM, Goodman SR, Breen GA (2011) Early dysregulation of the mitochondrial proteome in a mouse model of Alzheimer’s disease. J Proteome 74:466–479

    Article  CAS  Google Scholar 

  119. Manczak M, Park BS, Jung Y, Reddy PH (2004) Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease: implications for early mitochondrial dysfunction and oxidative damage. NeuroMolecular Med 5:147–162

    Article  CAS  PubMed  Google Scholar 

  120. Reddy PH, McWeeney S, Park BS, Manczak M, Gutala RV, Partovi D, Jung Y, Yau V et al (2004) Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer’s disease. Hum Mol Genet 13:1225–1240

    Article  CAS  PubMed  Google Scholar 

  121. Di Domenico F, Sultana R, Barone E, Perluigi M, Cini C, Mancuso C, Cai J, Pierce WM et al (2011) Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer’s disease subjects. J Proteome 74:1091–1103

    Article  CAS  Google Scholar 

  122. Oh H, Madison C, Baker S, Rabinovici G, Jagust W (2016) Dynamic relationships between age, amyloid-β deposition, and glucose metabolism link to the regional vulnerability to Alzheimer’s disease. Brain 139:2275–2289

    Article  PubMed  PubMed Central  Google Scholar 

  123. Richter F, Meurers BH, Zhu C, Medvedeva VP, Chesselet MF (2009) Neurons express hemoglobin alpha- and beta-chains in rat and human brains. J Comp Neurol 515:538–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Biagioli M, Pinto M, Cesselli D, Zaninello M, Lazarevic D, Roncaglia P, Simone R, Vlachouli C et al (2009) Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells. Proc Natl Acad Sci U S A 106:15454–15459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Shephard F, Greville-Heygate O, Marsh O, Anderson S, Chakrabarti L (2014) A mitochondrial location for haemoglobins—dynamic distribution in ageing and Parkinson’s disease. Mitochondrion 14:64–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Li X, Wu Z, Wang Y, Mei Q, Fu X, Han W (2013) Characterization of adult α- and β-globin elevated by hydrogen peroxide in cervical cancer cells that play a cytoprotective role against oxidative insults. PLoS One 8:e54342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ferrer I, Gómez A, Carmona M, Huesa G, Porta S, Riera-Codina M, Biagioli M, Gustincich S et al (2011) Neuronal hemoglobin is reduced in Alzheimer’s disease, argyrophilic grain disease, Parkinson’s disease, and dementia with Lewy bodies. J Alzheimers Dis 23:537–550

    CAS  PubMed  Google Scholar 

  128. Spellman DS, Wildsmith KR, Honigberg LA, Tuefferd M, Baker D, Raghavan N, Nairn AC, Croteau P et al, Alzheimer’s Disease Neuroimaging Initiative; Foundation for NIH (FNIH) Biomarkers Consortium CSF Proteomics Project Team (2015) Development and evaluation of a multiplexed mass spectrometry based assay for measuring candidate peptide biomarkers in Alzheimer’s Disease Neuroimaging Initiative (ADNI) CSF. Proteomics Clin Appl 9:715–731

  129. Shah RC, Buchman AS, Wilson RS, Leurgans SE, Bennett DA (2011) Hemoglobin level in older persons and incident Alzheimer disease: prospective cohort analysis. Neurology 77:219–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Arrigo AP, Simon S, Gibert B, Kretz-Remy C, Nivon M, Czekalla A, Guillet D, Moulin M et al (2007) Hsp27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets. FEBS Lett 581:3665–3674

    Article  CAS  PubMed  Google Scholar 

  131. Bennardini F, Wrzosek A, Chiesi M (1992) Alpha-B crystallin in cardiac tissue. Association with actin and desmin filaments. Circ Res 71:288–294

    Article  CAS  PubMed  Google Scholar 

  132. Golenhofen N, Htun P, Ness W, Koob R, Schaper W, Drenckhahn D (1999) Binding of the stress protein alpha B-crystallin to cardiac myofibrils correlates with the degree of myocardial damage during ischemia/reperfusion in vivo. J Mol Cell Cardiol 31:569–580

    Article  CAS  PubMed  Google Scholar 

  133. Nicholl ID, Quinlan RA (1994) Chaperone activity of alpha-crystallins modulates intermediate filament assembly. EMBO J 13:945–953

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Raman B, Ban T, Sakai M, Pasta SY, Ramakrishna T, Naiki H, Goto Y, Rao CM (2005) AlphaB-crystallin, a small heat-shock protein, prevents the amyloid fibril growth of an amyloid beta-peptide and beta2-microglobulin. Biochem J 392:573–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Moseley P (2000) Stress proteins and the immune response. Immunopharmacology 48:299–302

    Article  CAS  PubMed  Google Scholar 

  136. Iwaki T, Kume-Iwaki A, Liem RK, Goldman JE (1989) Alpha B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander’s disease brain. Cell 57:71–78

    Article  CAS  PubMed  Google Scholar 

  137. Ousman SS, Tomooka BH, van Noort JM, Wawrousek EF, O'Connor KC, Hafler DA, Sobel RA, Robinson WH et al (2007) Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature 448:474–479

    Article  CAS  PubMed  Google Scholar 

  138. Rothbard JB, Kurnellas MP, Brownell S, Adams CM, Su L, Axtell RC, Chen R, Fathman CG et al (2012) Therapeutic effects of systemic administration of chaperone αB-crystallin associated with binding proinflammatory plasma proteins. J Biol Chem 287:9708–9721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Steinman L, Rothbard JB, Kurnellas MP (2014) Janus faces of amyloid proteins in neuroinflammation. J Clin Immunol 34:S61–S63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Hanzel CE, Pichet-Binette A, Pimentel LS, Iulita MF, Allard S, Ducatenzeiler A, Do Carmo S, Cuello AC (2014) Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer’s disease. Neurobiol Aging 35:2249–2262

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The Cuello laboratory is grateful for the unrestricted support received from Dr. Alan Frosst, the Frosst family, and Merck Canada. This study was supported by the Canadian Institute of Health Research (MOP-102752 to A.C.C.). This work was also made possible through the Roskamp Foundation. S.D.C. is the holder of the Charles E. Frosst/Merck Research Associate position. M.F.I. was the recipient of a Biomedical Doctoral Award from the Alzheimer Society of Canada (2011–2014). A.C.C. is the holder of the Charles E. Frosst/Merck-endowed Chair in Pharmacology and a member of the Canadian Consortium on Neurodegeneration in Aging.

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S.D.C., F.C., and A.C.C. designed and supervised the research. S.D.C., G.C., T.P., J.R., M.F.I., and A.D. performed research. S.D.C., G.C., T.P., and M.F.I. analyzed data. S.D.C., G.C., F.C., and A.C.C. wrote the manuscript.

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Correspondence to A. Claudio Cuello.

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All procedures were approved by the Animal Care Committee of McGill University and conformed to guidelines set down by the Canadian Council of Animal Care.

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One Sentence Summary: Brain proteome changes throughout amyloid pathology progression

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Do Carmo, S., Crynen, G., Paradis, T. et al. Hippocampal Proteomic Analysis Reveals Distinct Pathway Deregulation Profiles at Early and Late Stages in a Rat Model of Alzheimer’s-Like Amyloid Pathology. Mol Neurobiol 55, 3451–3476 (2018). https://doi.org/10.1007/s12035-017-0580-9

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